Search

Abstract Introduction The aim of this study is to identify the profiles of young people who use drugs (YPUD) and their exposure to HIV risks in the 3 main cities of Vietnam, Haiphong, Hanoi, and Ho Chi Minh City (HCMC), in order to design a community-based intervention to prevent HIV. Methods A survey using respondent-driven sampling (RDS) was conducted among YPUD aged 16–24. Participants were eligible if they reported drug use, confirmed by a urine test. After obtaining informed consent, they were screened for HIV/HCV and assessed using face-to-face questionnaires and self-report. A cluster analysis was conducted, taking into account risk behaviors and confirmed HIV-positive status. Results Seven hundred and three YPUD aged 16–24 were recruited between October 2016 and February 2017, 584 of whom were included in the final analysis. Median age was 21 (17.7, 23.0); 79% were male, 18% female, and 2% transgender. Methamphetamines use was reported by 77%, followed by cannabis (51%) and heroin (17%); polydrug use was common; 15% had “ever” injected drugs. HIV prevalence was 7%. Among all participants, 48% reported non-consistent condom use and 1% reported needle/syringe sharing during the previous month. Four distinct profiles of HIV risk behaviors were identified: The high multiple-risk group mixed unsafe drug use with unsafe sexual practices and had higher prevalence of HIV; the second group practiced high-risk sex with non-consistent condom combined with methamphetamine use; the third group was a moderate-risk group with limited unsafe sexual practices; and the fourth was considered at “low-risk” as reportedly, most never had sex and never injected. The highest risk group included more female YPUD, living in HCMC, who used heroin and had unsafe sex with their regular partners. The second high-risk group included most of the MSM and all transgender people and frequently reported mental health disorders. Conclusions The profiles of YPUD who are at risk of HIV vary according to age, location, and population group. Injecting YPUD are the most exposed to risk and need immediate attention. Sexual exposure to HIV is very common. Mental health is a major concern. Interventions need to be integrated in a differentiated but holistic approach.

Abstract Sensing-based deep brain stimulation should optimally consider both the motor and neuropsychiatric domain to maximize quality of life of Parkinson’s disease (PD) patients. Here we characterize the neurophysiological properties of the subthalamic nucleus (STN) in 69 PD patients using a newly established neurophysiological gradient metric and contextualize it with motor symptoms and apathy. We could evidence a STN power gradient that holds most of the spectral information between 5 and 30 Hz spanning along the dorsal-ventral axis. It shows elevated power in the sub-beta range (8-12 Hz) toward the ventral STN, and elevated dorsal beta power (16–24 Hz) indicative for the hemispheres contralateral to the more affected hemi-body side. The rigidity response to DBS was highest dorsally on the axis. Importantly, apathetic symptoms can be related to reduced ventral alpha power. In conclusion, the STN spectral gradient may inform about the motor and neuropsychiatric domain, supporting integrative closed-loop strategies.

Objective: Acute electrical stimulation of the common peroneal nerve (cPNS) has been shown to cause an immediate reduction in systolic blood pressure (SBP) in spontaneous hypertense rats (SHR), but the effect of this treatment in sub-chronic ambulatory SBP is unknown. Here we developed an implantable wireless WNClip neural stimulator to test the efficacy of 5-week cPNS as a treatment for hypertension. Results: Daily cPNS 2 Hz monophasic stimulation at threshold for 8 minutes every day for five weeks, reduced SBP in WKY animals by −4 mm Hg, and in SHR animals by −21 mmHg in week 5 (p < 0.01). Ambulatory SBP measured daily recorded approximately twenty-four hours after the cPNS treatment, showed a significant reduction from the first (176.6 ± 24.1 mm Hg; n = 5) to the last week of treatment (165.7± 42.7 mm Hg; n = 4), a −9 mm Hg reduction (p < 0.01). Evaluation of heart rate during the treatment showed no significant difference caused by the daily 8-minute cPNS. Conclusions: Electrical stimulation of the common peroneal nerve induced a reduction in SBP that is comparable to that reportedly achieved pharmacologically by ACE inhibitor Ramipril, or by renal denervation procedures. These results support the notion that neuromodulation of the common peroneal nerve can serve as an alternative treatment for drug resistant hypertension.

Abstract Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging unsolved problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign tasks, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 19 new homo-oligomers and structurally recombined them to make 24 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system have identical or nearly identical backbones, and hence are ideal building blocks for generating and functionalizing larger symmetric and pseudosymmetric assemblies.

Abstract Clinical studies of the urinary tract microbiome, termed urobiome, suggest a direct, antibiotic-dependent, impact of the urobiome on kidney physiology. However, evidence for kidney bacteria comes from indirect sources or infected tissue. Further, it is unclear how antibiotics impact kidney bacteria. Here we show direct evidence for the presence of bacteria in the kidneys, with microniches in nephrons. In murine kidneys, administration of cefazolin, a commonly used perioperative antibiotic, led to a loss of uroprotective Lactobacillus spp. and proliferation of Enterobacteriaceae (which includes many known uropathogens). This effect was dependent on treatment duration, with recovery post treatment. Uroprotective L. crispatus and a strain of stone-associated E. coli differentially influenced calcium oxalate (CaOx) crystallization through the incorporation of CaOx inhibitors or promoters, respectively. In humans, microbial signatures were identified in the kidney, with unique niches between the glomeruli and tubules, established through RNA sequencing analysis and direct imaging of two independent populations. Collectively, findings support the hypothesis that the kidneys harbor a stable and antibiotic-responsive microbiota that can influence CaOx lithogenesis. The presence of unique, age-dependent microbial signatures in the glomeruli and tubuli carry implications for non-infectious kidney diseases.

Background: Computational analysis of routine electroencephalogram (rEEG) could improve the accuracy of epilepsy diagnosis. We aim to systematically assess the diagnostic performances of computed biomarkers for epilepsy in individuals undergoing rEEG. Methods: We searched MEDLINE, EMBASE, EBM reviews, IEEE Explore and the grey literature for studies published between January 1961 and December 2022. We included studies reporting a computational method to diagnose epilepsy based on rEEG without relying on the identification of interictal epileptiform discharges or seizures. Diagnosis of epilepsy as per a treating physician was the reference standard. We assessed the risk of bias using an adapted QUADAS-2 tool. Results: We screened 10 166 studies, and 37 were included. The sample size ranged from 8 to 192 (mean=54). The computed biomarkers were based on linear (43%), non-linear (27%), connectivity (38%), and convolutional neural networks (10%) models. The risk of bias was high or unclear in all studies, more commonly from spectrum effect and data leakage. Diagnostic accuracy ranged between 64% and 100%. We observed high methodological heterogeneity, preventing pooling of accuracy measures. Conclusion: The current literature provides insufficient evidence to reliably assess the diagnostic yield of computational analysis of rEEG. Significance: We provide guidelines regarding patient selection, reference standard, algorithms, and performance validation.

Abstract Objective Non‐invasive biomarkers have recently shown promise for seizure forecasting in people with epilepsy. In this work, we developed a seizure‐day forecasting algorithm based on nocturnal sleep features acquired using a smart shirt. Methods Seventy‐eight individuals with epilepsy admitted to the Centre hospitalier de l'Université de Montréal epilepsy monitoring unit wore the Hexoskin biometric smart shirt during their stay. The shirt continuously measures electrocardiography, respiratory, and accelerometry activity. Ten sleep features, including sleep efficiency, sleep latency, sleep duration, time spent in non‐rapid eye movement sleep (NREM) and rapid eye movement sleep (REM), wakefulness after sleep onset, average heart and breathing rates, high‐frequency heart rate variability, and the number of position changes, were automatically computed using the Hexoskin sleep algorithm. Each night's features were then normalized using a reference night for each patient. A support vector machine classifier was trained for pseudo‐prospective seizure‐day forecasting, with forecasting horizons of 16‐ and 24‐h to include both diurnal and nocturnal seizures (24‐h) or diurnal seizures only (16‐h). The algorithm's performance was assessed using a nested leave‐one‐patient‐out cross‐validation approach. Results Improvement over chance (IoC) performances were achieved for 48.7% and 40% of patients with the 16‐ and 24‐h forecasting horizons, respectively. For patients with IoC performances, the proposed algorithm reached mean IoC, sensitivity and time in warning of 34.3%, 86.0%, and 51.7%, respectively for the 16‐h horizon, and 34.2%, 64.4% and 30.2%, respectively, for the 24‐h horizon. Significance Smart shirt‐based nocturnal sleep analysis holds promise as a non‐invasive approach for seizure‐day forecasting in a subset of people with epilepsy. Further investigations, particularly in a residential setting with long‐term recordings, could pave the way for the development of innovative and practical seizure forecasting devices. Plain Language Summary Seizure forecasting with wearable devices may improve the quality of life of people living with epilepsy who experience unpredictable, recurrent seizures. In this study, we have developed a seizure forecasting algorithm using sleep characteristics obtained from a smart shirt worn at night by a large number of hospitalized patients with epilepsy (78). A daily seizure forecast was generated following each night using machine learning methods. Our results show that around half of people with epilepsy may benefit from such an approach.

Abstract Background Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. Methods One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. Discussion SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. Trial registration Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Abstract Psychiatry has traditionally focused on the study of neurons and neurotransmitter physiology in the pathophysiology and treatment of psychiatric disorders. A growing literature highlights REDOX imbalance (a state in which demand for antioxidants surpasses their bioavailability) as a common pathophysiology for a diverse array of brain conditions (e.g., trichotillomania, schizophrenia, autism, Parkinson’s disease). REDOX imbalance is typically measured via plasma glutathione, as glutathione is critical to the adaptive antioxidant response in the brain. Accordingly, glutathione, its precursors, and/or metabolites serve as biomarkers of disease risk, therapeutic targets, and measures of treatment response. However, as with any emerging field, there are currently several different methods for collection, processing, storage, and calculation of summary measures of plasma glutathione metabolism, within and between preclinical and clinical research. The lack of evidence-based best-practice methodology hampers reproducibility (preclinical or clinical), and translation (between preclinical and clinical work). To address this methodological need, here we used a repeated measures within-subject design to investigate how sample preparation (type of anticoagulant used during blood collection, deproteinization status, and storage temperature) affects plasma glutathione levels. Accordingly, we collected whole blood from mice (N = 13), and then, using a commercially available kit, quantified glutathione in plasma stored in four different ways. Presuming that these preparation conditions and post-processing calculations are unimportant, we would expect to see no difference in glutathione levels and summary measures from the same sample. However, we found each of these variables to significantly alter quantified glutathione levels. Accordingly, we propose a vital, gold-standard methodology for both sample collection, processing, and storage of plasma used for glutathione quantification and for summary calculations of glutathione that can be used preclinically and clinically, thus yielding more streamlined translation.

The recent U.S. Supreme Court decisions "Students for Fair Admissions, Inc. v. President and Fellows of Harvard College" (2023) and "Students for Fair Admissions, Inc. v. University of North Carolina et al." (2023), hereafter collectively referred to as "SFFA v. Harvard," have garnered attention, especially among higher education administrators (Schermele, 2023). This attention is, of course, justified because the decisions represent a major shift in the way the U.S. Supreme Court has approached race-conscious admissions. The court has changed direction in its willingness to accept the educational benefits of diversity as a justification for utilizing race in admissions programs. In this article, the authors take a look at the "SFFA v. Harvard" decision, offer some context for the role of U.S. Supreme Court decisions, and discuss implications for higher education practitioners.

Coronary artery vasospasm (CAV) is characterized by transient constriction of epicardial coronary arteries leading to angina. Its disease mechanisms are multifactorial but has centered mostly on endothelial dysfunction and smooth muscle hyperreactivity. To facilitate the investigation of these mechanisms in cell culture, we generated and characterized three induced pluripotent stem cell (iPSC) lines from patients with CAV. These lines demonstrated normal morphology and karyotypes, robust expression of pluripotency markers, and ability for tri-lineage differentiation. Further differentiation of these cell lines into endothelial and smooth muscle cells will allow mechanistic investigation of their relative contributions to CAV in cell culture.

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8% ± 1.8% and 85.9% ± 6.1% (p < 0.05) at 1, 6 and 7 week post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 µg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 µg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity, and energy intake in DIO rats. Chronic 4V OT reduced BW gain by −7.2 ± 9.6 g and −14.1 ± 8.8 g in sham and denervated rats (p < 0.05 vs. vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (p < 0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

Dietary fiber supplements are a strategy to close the ‘fiber gap’ and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; n = 15) relative to non-fermentable microcrystalline cellulose (MCC; n = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (p

Bacterial biofilms represent a significant challenge in both clinical and industrial settings because of their robust nature and resistance to antimicrobials. Biofilms are formed by microorganisms that produce an exopolysaccharide matrix, protecting function and supporting for nutrients. Among the various bacterial species capable of forming biofilms, Staphylococcus epidermidis, a commensal organism found on human skin and mucous membranes, has emerged as a prominent opportunistic pathogen, when introduced into the body via medical devices, such as catheters, prosthetic joints, and heart valves. The formation of biofilms by S. epidermidis on these surfaces facilitates colonization and provides protection against host immune responses and antibiotic therapies, leading to persistent and difficult-to-treat infections.The possible involvement of biofilms for breast oncogenesis has recently created the curiosity. This paper therefore delves into S. epidermidis biofilm involvement in breast cancer. S. epidermidis biofilms can create a sustained inflammatory environment through their metabolites and can break DNA in breast tissue, promoting cellular proliferation, angiogenesis, and genetic instability.Preventing biofilm formation primarily involves preventing bacterial proliferation using prophylactic measures and sterilization of medical devices and equipment. In cancer treatment, common modalities include chemotherapy, surgery, immunotherapy, alkylating agents, and various anticancer drugs. Understanding the relationship between anticancer drugs and bacterial biofilms is crucial, especially for those undergoing cancer treatment who may be at increased risk of bacterial infections, for improving patient outcomes. By elucidating these interactions, strategies to prevent or disrupt biofilm formation, thereby reducing the incidence of infections associated with medical devices and implants, can be identified.

A new frontier in tuning the electromagnetic response of carbon-based materials, particularly carbon nanotubes, consists in adding metallic clusters or nanoparticles at their external surface. This allows to change optical, dielectric and magnetic properties with potential applications in electronics and telecommunications for aeronautics. By resorting to first principles dynamical simulations, we provide a microscopic picture of the interaction at finite temperature between a carbon nanotube and Co aggregates mimicking the experimental coverage. The electronic structure evolution provides the absorption spectrum and the dielectric function for comparison with experiments and guidelines for tuning these composite systems.

Abstract In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p

Abstract Signal processing by intracellular kinases controls near all biological processes but how signal pathway functions evolve with changed cellular context is poorly understood. Functional specificity of c-Jun N-terminal Kinases (JNK) are partly encoded by signal strength. Here we reveal that intracellular pH (pHi) is a significant component of the JNK network and defines signal response to specific stimuli. We show pHi regulates JNK activity in response to cell stress, with the relationship between pHi and JNK activity dependent on specific stimuli and upstream kinases activated. Using the optogenetic clustering tag CRY2, we show that an increase in pHi promotes the light-induced phase transition of ASK1 to augment JNK activation. While increased pHi similarly promoted CRY2-tagged JNK2 to form light-induced condensates, this attenuated JNK activity. Mathematical modelling of feedback signalling incorporating pHi and differential contributions by ASK1 and JNK2 condensates was sufficient to delineate signal responses to specific stimuli. Taking pHi and ASK1/JNK2 signal contributions into consideration may delineate oncogenic versus tumour suppressive JNK functions and cancer cell drug responses.

Abstract Background In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes. Methods Design: We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam. Participants: Sexually active MSM (n=564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants (n=20) in each arm will be selected for longitudinal qualitative interviews; an additional subset (n=48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders (n=35). Intervention: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use. Outcomes: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders. Discussion This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings. Trial registration NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

Abstract Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Abstract This study in older hospitalized patients with heart failure with reduced ejection fraction (HFrEF) aimed to examine the prevalence of beta-blocker prescription and its associated factors. A total of 190 participants were recruited from July 2019 to July 2020. The inclusion criteria included: (1) aged ≥ 60 years, (2) having a diagnosis of chronic HFrEF in the medical records, (3) hospitalized for at least 48 h. The participants had a mean age of 75.5 ± 9.1, and 46.8% were female. Of these, 55.3% were prescribed beta-blockers during admission. To explore the factors associated with beta-blocker prescription, multivariable logistic regression analysis was applied and the results were presented as odds ratios (OR) and 95% confidence intervals (CI). On multivariate logistic regression models, higher NYHA classes (OR 0.49, 95%CI 0.26–0.94), chronic obstructive pulmonary disease (OR 0.17, 95% CI 0.04–0.85), chronic kidney disease (OR 0.40, 95% CI 0.19–0.83), and heart rate under 65 (OR 0.34, 95% CI 0.12–0.98) were associated with a reduced likelihood of prescription. In this study, we found a low rate of beta-blocker prescriptions, with only around half of the participants being prescribed beta-blockers. Further studies are needed to examine the reasons for the under-prescription of beta-blockers, and to evaluate the long-term benefits of beta-blockers in elderly patients with HFrEF in this population.

Abstract Background Evidence-based interventions (EBIs) often address normative behaviors. If a behavior is also common among clinicians, they may be skeptical about the necessity or effectiveness of an EBI. Alternatively, clinicians’ attitudes and behaviors may be misaligned, or they may lack the knowledge and self-efficacy to deliver the EBI. Several EBIs address unhealthy alcohol use, a common and often culturally acceptable behavior. But unhealthy alcohol use may be particularly harmful to people with HIV (PWH). Here, we present an implementation trial using an experiential implementation strategy to address clinicians’ knowledge, attitudes, and behaviors. Clinicians receive the experiential intervention before they begin delivering an evidence-based brief alcohol intervention (BAI) to PWH with unhealthy alcohol use. Methods Design: In this hybrid type 3 implementation-effectiveness cluster randomized controlled trial, ART clinics (n = 30) will be randomized 1:1 to facilitation, a flexible strategy to address implementation barriers, or facilitation plus the experiential brief alcohol intervention (EBAI). In the EBAI arm, clinicians, irrespective of their alcohol use, will be offered the BAI as experiential learning. EBAI will address clinicians’ alcohol-related attitudes and behaviors and increase their knowledge and confidence to deliver the BAI. Participants: ART clinic staff will be enrolled and assessed at pre-BAI training, post-BAI training, 3, 12, and 24 months. All PWH at the ART clinics who screen positive for unhealthy alcohol use will be offered the BAI. A subset of PWH (n = 810) will be enrolled and assessed at baseline, 3, and 12 months. Outcomes: We will compare implementation outcomes (acceptability, fidelity, penetration, costs, and sustainability) and effectiveness outcomes (viral suppression and alcohol use) between the two arms. We will assess the impact of site-level characteristics on scaling-up the BAI. We will also evaluate how experiencing the BAI affected clinical staff’s alcohol use and clinic-level alcohol expectations in the EBAI arm. Discussion This trial contributes to implementation science by testing a novel strategy to implement a behavior change intervention in a setting in which clinicians themselves may engage in the behavior. Experiential learning may be useful to address normative and difficult to change lifestyle behaviors that contribute to chronic diseases. Trial Registration NCT06358885 (04/10/2024), https://clinicaltrials.gov/study/NCT06358885 .

Density of microalgae is critical information for production of algae in a closed cultivation system since it can be used to optimally control their growth rate, biomass concentration and quality of the products. Given advancement in image processing techniques and thanks to low-cost camera sensors, image based methods are increasingly widely utilized to indirectly estimate the density. Advantages of the image based techniques include being less invasive and more nondestructive and biosecured. However, most of the existing techniques rely on averaging all pixels of a microalgae image, which may eliminate crucial information of their spatial correlation. Therefore, in this work we propose to exploit a convolutional neural network (CNN) to efficiently extract information from the microalgae images, which are then employed to regress the density. Interestingly, the proposed deep CNN regression model accepts the whole color image as its input while the density is calculated in the output. The proposed CNN regression architecture was validated in real-world experiments where the microalgal strain Chlorella vulgaris was cultured and their images were captured by our low-cost camera sensor system. The obtained results demonstrate that the averaged estimation accuracy of the proposed model is 99.45% (± 0.68%) while the R2 value between the density predictions and the ground truths is 0.9997, which is highly accurate and practical.

ABSTRACT Mycobacterium tuberculosis (Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. By contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid- and cholesterol-associated pathways including the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived high-density lipoprotein from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to Mycobacterium tuberculosis often results in latent TB latent infection (LTBI), subpopulations exist that are either resistant to infection or contain Mtb with interferon-gamma (IFNγ)-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate the mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.

Background: Inflammation has long been a key tenet in the diagnosis and management of malignancies, likely contributing to cancer incidence, staging, and progression. Systemic inflammation, in particular, is often elevated prior to and during cancer development. Systemic inflammation in the context of cancer diagnosis and monitoring is measured by various inflammatory indexes such as the systemic inflammatory response index (SIRI), plasma-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and neutrophil-to-lymphocyte ratio (NLR). We set out to determine the relationship between pre- and post-treatment levels of these inflammatory indexes and the prognosis and outcomes of oropharyngeal cancer (OPC). Methods: A retrospective chart review was performed of 172 patients with OPC who underwent treatment for oropharyngeal cancer at University Medical Center in Lubbock, TX between May 2013 to May 2023. Sites of primary cancer were obtained through chart review. HPV infection status and differentiation of the tumor were noted for each patient. Treatment modalities were classified as surgery, radiation, chemotherapy, or concurrent chemotherapy and radiation. Treatment outcomes were classified based on recurrence and death secondary to disease. The relationships between treatment outcome and the described inflammatory indexes were evaluated. Appropriate parametric tests were selected based on the large number of variables. Results: Pre-treatment SIRI and Albumin levels were positively predictive in determining locoregional recurrence (p = 0.031 and p = 0.039). NLR, SII, and SIRI levels taken at three months post-treatment were also found to be positively predictive of locoregional recurrence (p = 0.005, p < 0.0005, and p = 0.007). SIRI taken at six months post-treatment was also found to be positively predictive of locoregional recurrence (p = 0.008). SII at six months post-treatment was found to be positively predictive of survival (p = 0.027). Conclusion: This study suggested that post-treatment levels of several inflammatory indexes, particularly SIRI, NLR, and SII, may be useful in determining the long-term outlook and recurrence of head and neck cancer following treatment.

Curricula in school often do not prepare students adequately for the kinds of critical and creative thinking that they will need in their careers and lives. Part of the problem is that the characteristics of real-world problems differ greatly from the characteristics of many curricular activities, and so what the students learn in school about critical and creative thinking may fail when generalized to everyday problems. We suggest that extracurricular activities, such as in aspects of musical and athletic training, often prepare students better for real-world challenges. We describe the kinds of methods that can be used in curricular instruction to better prepare students for the challenges of the everyday world.

In an effort to pursue a green synthesis approach, the biosynthesis of nano-silver (nAg) using plant extracts has garnered significant attention, particularly for its antimicrobial resistance and medical applications, which have been the focus of numerous studies. However, there remains a gap in surface catalytic studies, especially regarding the hydrogenation of 4-nitrophenol. While some studies have addressed catalytic kinetics, thermodynamic aspects have been largely overlooked, leaving the catalytic mechanisms of biosynthesized nAg unclear.In this context, the present work offers a straightforward, eco-friendly, and efficient protocol to obtain nano-silver inspired by Musa paradisiaca L. peel extract. This nAg serves multiple purposes, including antimicrobial resistance and as an eco-catalyst for hydrogenation. Predominantly consisting of zero-valent silver with anisotropic polyhedral shapes, mainly decahedra with an edge length of 50 nm, this nAg demonstrated effective antimicrobial action against both S. aureus and E. coli bacteria.More importantly, both kinetic and thermodynamic studies on the hydrogenation of 4-nitrophenol to 4-aminophenol catalyzed by this bio-inspired nAg revealed that the rate-limiting step is not diffusion-limited. Instead, the adsorbed hydrogen and 4-nitrophenolate react together via electron transfer on the surface of the nAg. The activation energy of 26.24 kJ mol−1 indicates a highly efficient eco-catalyst for such hydrogenation processes.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P

IntroductionOperculo-insular epilepsy (OIE) is a rare condition amenable to surgery in well-selected cases. Despite the high rate of neurological complications associated with OIE surgery, most postoperative deficits recover fully and rapidly. We provide insights into this peculiar pattern of functional recovery by investigating the longitudinal reorganization of structural networks after surgery for OIE in 10 patients.MethodsStructural T1 and diffusion-weighted MRIs were performed before surgery (t0) and at 6 months (t1) and 12 months (t2) postoperatively. These images were processed with an original, comprehensive structural connectivity pipeline. Using our method, we performed comparisons between the t0 and t1 timepoints and between the t1 and t2 timepoints to characterize the progressive structural remodeling.ResultsWe found a widespread pattern of postoperative changes primarily in the surgical hemisphere, most of which consisted of reductions in connectivity strength (CS) and regional graph theoretic measures (rGTM) that reflect local connectivity. We also observed increases in CS and rGTMs predominantly in regions located near the resection cavity and in the contralateral healthy hemisphere. Finally, most structural changes arose in the first six months following surgery (i.e., between t0 and t1).DiscussionTo our knowledge, this study provides the first description of postoperative structural connectivity changes following surgery for OIE. The ipsilateral reductions in connectivity unveiled by our analysis may result from the reversal of seizure-related structural alterations following postoperative seizure control. Moreover, the strengthening of connections in peri-resection areas and in the contralateral hemisphere may be compatible with compensatory structural plasticity, a process that could contribute to the recovery of functions seen following operculo-insular resections for focal epilepsy.

Abstract Background Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Streptococcus pneumoniae and Staphylococcus aureus are major bacterial causes of lower respiratory tract infections (LRTIs) globally, leading to substantial morbidity and mortality. The rapid increase of antimicrobial resistance (AMR) in these pathogens poses significant challenges for their effective antibiotic therapy. In low-resourced settings, patients with LRTIs are prescribed antibiotics empirically while awaiting several days for culture results. Rapid pathogen and AMR gene detection could prompt optimal antibiotic use and improve outcomes. Methods Here, we developed multiplex quantitative real-time PCR using EvaGreen dye and melting curve analysis to rapidly identify six major pathogens and fourteen AMR genes directly from respiratory samples. The reproducibility, linearity, limit of detection (LOD) of real-time PCR assays for pathogen detection were evaluated using DNA control mixes and spiked tracheal aspirate. The performance of RT-PCR assays was subsequently compared with the gold standard, conventional culture on 50 tracheal aspirate and sputum specimens of ICU patients. Results The sensitivity of RT-PCR assays was 100% for K. pneumoniae, A. baumannii, P. aeruginosa, E. coli and 63.6% for S. aureus and the specificity ranged from 87.5% to 97.6%. The kappa correlation values of all pathogens between the two methods varied from 0.63 to 0.95. The limit of detection of target bacteria was 1600 CFU/ml. The quantitative results from the PCR assays demonstrated 100% concordance with quantitative culture of tracheal aspirates. Compared to culture, PCR assays exhibited higher sensitivity in detecting mixed infections and S. pneumoniae. There was a high level of concordance between the detection of AMR gene and AMR phenotype in single infections. Conclusions Our multiplex quantitative RT-PCR assays are fast and simple, but sensitive and specific in detecting six bacterial pathogens of LRTIs and their antimicrobial resistance genes and should be further evaluated for clinical utility.

Abstract Utility of PI3Kα inhibitors like BYL719 is limited by the acquisition of genetic and non-genetic mechanisms of resistance which cause disease recurrence. Several combination therapies based on PI3K inhibition have been proposed, but a way to systematically prioritize them for breast cancer treatment is still missing. By integrating published and in-house studies, we have developed in silico models that quantitatively capture dynamics of PI3K signaling at the network-level under a BYL719-sensitive versus BYL719 resistant-cell state. Computational predictions show that signal rewiring to alternative components of the PI3K pathway promote resistance to BYL719 and identify PDK1 as the most effective co-target with PI3Kα rescuing sensitivity of resistant cells to BYL719. To explore whether PI3K pathway-independent mechanisms further contribute to BYL719 resistance, we performed phosphoproteomics and found that selection of high levels of the cell cycle regulator p21 unexpectedly promoted drug resistance in T47D cells. Functionally, high p21 levels favored repair of BYL719-induced DNA damage and bypass of the associated cellular senescence. Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer.

Abstract Background Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD. Methods Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models. Results Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found. Limitations This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores. Conclusions Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

The increasing global reliance on pesticides for agricultural pest control has raised significant environmental concerns, particularly due to inadequate monitoring of emerging chemicals in surface waters. This study addresses the potential contamination of aquatic ecosystems by developing and validating a method for detecting trace amounts of four recently registered fungicides: three succinate dehydrogenase inhibitors (fluopyram, penthiopyrad, pydiflumetofen) and fluopicolide, a structurally related fungicide. Employing QuEChERS-based sample extraction combined with ultra-high-performance liquid chromatography (UHPLC-MS-MS), this method achieves detection limits of 0.1 to 0.2 μg/L, with recovery rates between 90% and 110%, and intra-day relative standard deviation values well within the acceptable range of less than 20%. Applied to surface grab water samples from the greater Melbourne area, Australia, the method successfully identified all four fungicides at trace levels, including a notable high concentration of fluopyram (7.3 μg/L) during autumn, with the others intermittently detected at lower concentrations. This study represents the first documented instance of quantifiable detections of these four fungicides in Australian surface water systems. Given their high toxicity to several organisms and the limited global data on these substances, our findings underscore the critical need for continuous monitoring to inform strategies to safeguard aquatic ecosystems from these chemicals.

Abstract Soft materials in nature are formed through reversible supramolecular assembly of biological polymers into dynamic hierarchical networks. Rational design has led to self-assembling peptides with structural similarities to natural materials. However, recreating the dynamic functional properties inherent to natural systems remains challenging. Here we report the discovery of a short peptide based on the tryptophan zipper (trpzip) motif, that shows multiscale hierarchical ordering that leads to emergent dynamic properties. Trpzip hydrogels are antimicrobial and self-healing, with tunable viscoelasticity and unique yield-stress properties that allow immediate harvest of embedded cells through a flick of the wrist. This characteristic makes Trpzip hydrogels amenable to syringe extrusion, which we demonstrate with examples of cell delivery and bioprinting. Trpzip hydrogels display innate bioactivity, allowing propagation of human intestinal organoids with apical-basal polarization. Considering these extensive attributes, we anticipate the Trpzip motif will prove a versatile building block for supramolecular assembly of soft materials for biotechnology and medicine.

ABSTRACT: Background: Osteosarcoma is the most common primary bone tumor in children. While the humerus is the third most common anatomic location, it is the most common site for fractures. Our objective is to characterize magnetic resonance imaging (MRI) features of humerus osteosarcoma in children and with respect to risk of sustaining a pathologic fracture. Methods: Children with histologically confirmed humerus osteosarcoma, who underwent preoperative MRI (2008-2023) were included. Two radiologists retrospectively reviewed all MRIs to determine medullary (skip lesions and trans-epiphyseal tumor), joint, and extraosseous (muscle, neurovasculature, and lymphadenopathy) disease. Tumor volumes were measured at diagnosis and after neoadjuvant chemotherapy, and findings between those with and without fractures were compared. Results: This study included 25 children (10 boys, 15 girls; mean age: 12.9 ± 4.2 years), 9 (36%) with (6 at diagnosis, 3 during treatment) and 16 (64%) without fractures. Radiologists’ agreement on various MRI characteristics including bone, joint, muscle, and neurovascular involvement of humerus osteosarcoma ranged between 60 and 100%. The most common findings included trans-epiphyseal tumor (80%), involvement of the long head of the biceps tendon (76%), and axillary neurovasculature (72%). Although tumor volumes were smaller in patients with (104 cm3, interquartile range [IQR]: 68-116) than without fractures (136 cm3, IQR: 100-216), this difference did not reach significance (p = .07); no other findings differed between the groups (p > .05). At a median follow-up of 17 months (IQR: 7-55), 52% relapsed, but no significant association was found between relapse and fracture (p = .69). Conclusions: Over a third of the patients with humerus osteosarcoma had pathologic fractures in our study group, but these did not significantly associate with larger tumor size, specific MRI features, or increased risk for disease relapse. Key Concepts: (1) The most common MRI findings in children with humerus osteosarcoma were trans-epiphyseal disease, followed by extraosseous disease involving the long head of the biceps tendon and the axillary neurovasculature. (2) The lack of significant differences between fracture and nonfracture groups in terms of serum biomarkers, histologic subtype and treatment response, MRI findings and outcome suggest that these fractures may result from a combination of tumor-related and patient-specific factors, but do not significantly associate with increased risk for relapse. Level of Evidence: III, retrospective cohort study

ABSTRACTClimate change jeopardizes human health, global biodiversity, and sustainability of the biosphere. To make reliable predictions about climate change, scientists use Earth system models (ESMs) that integrate physical, chemical, and biological processes occurring on land, the oceans, and the atmosphere. Although critical for catalyzing coupled biogeochemical processes, microorganisms have traditionally been left out of ESMs. Here, we generate a “top 10” list of priorities, opportunities, and challenges for the explicit integration of microorganisms into ESMs. We discuss the need for coarse-graining microbial information into functionally relevant categories, as well as the capacity for microorganisms to rapidly evolve in response to climate-change drivers. Microbiologists are uniquely positioned to collect novel and valuable information necessary for next-generation ESMs, but this requires data harmonization and transdisciplinary collaboration to effectively guide adaptation strategies and mitigation policy.

BackgroundRefractory (RSE) and super-refractory status epilepticus (SRSE) are serious neurological conditions requiring aggressive management. Beyond anesthetic agents, there is a lack of evidence guiding management in these patients. This systematic review and individual participant data meta-analysis (IPDMA) seeks to evaluate and compare the currently available surgical techniques for the acute treatment of RSE and SRSE.MethodsA systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Participant Data (PRISMA-IPD). Only patients who underwent surgery while in RSE and SRSE were included. Descriptive statistics were used to compare various subgroups. Multivariable logistic regression models were constructed to identify predictors of status epilepticus (SE) cessation, long-term overall seizure freedom, and favorable functional outcome (i.e., modified Rankin score of 0–2) at last follow-up.ResultsA total of 87 studies including 161 participants were included. Resective surgery tended to achieve better SE cessation rate (93.9%) compared to non-resective techniques (83.9%), but this did not reach significance (p = 0.071). Resective techniques were also more likely to achieve seizure freedom (69.1% vs. 34.4%, p =

Abstract The ecological and genetic changes that underlie the evolution of host–microbe interactions remain elusive, primarily due to challenges in disentangling the variables that alter microbiome composition. To understand the impact of host habitat, host genetics, and evolutionary history on microbial community structure, we examined gut microbiomes of river‐ and three cave‐adapted morphotypes of the Mexican tetra, Astyanax mexicanus, in their natural environments and under controlled laboratory conditions. Field‐collected samples were dominated by very few taxa and showed considerable interindividual variation. We found that lab‐reared fish exhibited increased microbiome richness and distinct composition compared to their wild counterparts, underscoring the significant influence of habitat. Most notably, however, we found that morphotypes reared on the same diet throughout life developed distinct microbiomes suggesting that genetic loci resulting from cavefish evolution shape microbiome composition. We observed stable differences in Fusobacteriota abundance between morphotypes and demonstrated that this could be used as a trait for quantitative trait loci mapping to uncover the genetic basis of microbial community structure.